(R)-(-)-4-Cyano-3-hydroxybutyric acid esters are known to be easily converted to the active lactone site of Compactin, Mevalotin and Pravastatin which are attracting attention as a cholesterol depressant or an HMG-CoA reductase inhibitor. For example, it is reported that an (R)-4-cyano-3-hydroxybutyric acid ester with its hydroxyl group protected with a trialkylsilyl group, a tetrahydropyranyl group, etc. is hydrolyzed to form an amide which is then treated with an acid to obtain (R)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, as disclosed in U.S. Pat. No. 4,611,067.
It is also reported that an HMG-CoA reductase-inhibitor containing a phosphorus atom in the molecule thereof is obtained by halogen exchange- of methyl (S)-4-bromo-3-hydroxybutyrate prepared from isoascorbic acid with its hydroxyl group protected to obtain a corresponding iodide compound, which is then converted to a Wittig-Hornor reagent, followed by several additional steps, as disclosed in J. Med. Chem., Vol. 33, p. 2952 (1990).
EP 0 330 172 A discloses that a 4-cyano-3-hydroxybutyric acid derivative with its hydroxyl group protected is reacted with a malonic acid derivative to obtain a 6-cyano-3-oxohexanoic acid derivative, which is further led to a cholesterol biosynthesis inhibitor.
Known processes for synthesizing optically active 4-cyano-3-hydroxybutyric esters include a process comprising leading arabinose or ascorbic acid as an asymmetric source to methyl (S)-4-bromo-3-hydroxybutyrate according to the technique described in Acta Chem. Scand., Vol. B37, p. 341 (1983) and, after protecting the hydroxyl group with a tetrahydropyranyl group, a trialkylsilyl group, an alkyl group, etc., reacting the protected compound with sodium cyanide according to the technique as disclosed in U.S. Pat. No. 4,611,067 and a process comprising reacting L-ascorbic acid with hydrogen peroxide and calcium carbonate to form calcium L-threonate monohydrate and reacting the compound with hydrogen bromide to obtain a dibrominated compound, which is then led to a bromohydrin compound according to the process disclosed in Carbohydrate Res., Vol. 72, p. 301 (1979), followed by the above-mentioned protection of the hydroxyl group and reaction with sodium cyanide.
Preparation of ethyl 4-cyano-3-hydroxybutyrate is reported in Bull. Soc. Chim. Fr., (4) 33 (1923), 732, which comprises hydrolyzing 4-chloro-3-hydroxybutyronitrile to obtain a carboxylic acid, converting the carboxylic acid into its ethyl ester, and reacting the ethyl ester with potassium cyanide. However, the yield reported is low, and the literature makes no mention of optical activity.
The activity of the HMG-CoA reductase inhibitors is known to owe much to the steric configuration(s) of the hydroxyl group of the lactone moiety or of the two hydroxyl groups of the precursor .beta., .delta.-dihydroxycarboxylic acid.
For example, reduction in inhibitory activity depending on the steric configuration of the hydroxyl group is mentioned e.g., in J. Med. Chem., Vol. 30, p. 1858 (1987) and J. Org. Chem., vol. 51, p. 4931 (1986). That is, it is required to have high activity that the Steric configuration of the hydroxyl groups at the .beta.- and .delta.-positions of .beta.,.delta.-dihydroxycarboxylic acid forms a cis-configuration.
EP 0 024 348 A and U.S. Pat. Nos. 4,611,068 and 4,855,481 describe that the 4-hydroxyl group of the lactone ring of Compactin or Mevinolin must have an (R)-configuration to manifest the inhibitory activity and that conventional synthesis not only involves separation of the desired optically active compound which is accompanied with formation of an undesired isomer but also requires a very long reaction route.
In view of these reports made to date, the conventional processes have required protection of a hydroxyl group or separation of an optically active compound and involved many steps for obtaining a lactone ring moiety having high inhibitory activity. It has therefore been demanded to develop an economical synthetic process which consists of a short reaction route and is easy to carry out.